ClinVar Miner

Submissions for variant NM_000155.4(GALT):c.821-7A>G

gnomAD frequency: 0.00001  dbSNP: rs767337193
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000804257 SCV000944157 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2024-01-28 criteria provided, single submitter clinical testing This sequence change falls in intron 8 of the GALT gene. It does not directly change the encoded amino acid sequence of the GALT protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs767337193, gnomAD 0.06%). This variant has been observed in individual(s) with GALT-related conditions (PMID: 20547145, 25124065). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 649344). Studies have shown that this variant results in skipping of exon 9, but is expected to preserve the integrity of the reading-frame (PMID: 20547145). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002534776 SCV003741988 pathogenic Inborn genetic diseases 2021-09-24 criteria provided, single submitter clinical testing The c.821-7A>G intronic alteration results from an A to G substitution 7 nucleotides before coding exon 9 of the GALT gene. Based on data from gnomAD, the G allele has an overall frequency of <0.01% (12/282870) total alleles studied. The highest observed frequency was 0.06% (12/19952) of East Asian alleles. This alteration (reported as g.2621A>G) has been identified in the compound heterozygous state with a second pathogenic GALT variant in three Korean patients with galactosemia (Ko, 2010; Choi, 2014). This nucleotide position is not well conserved in available vertebrate species. RNA analysis has shown this variant alters splicing and causes skipping of exon 9 (Ko, 2010). In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Based on the available evidence, this alteration is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000804257 SCV004241321 likely pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2023-12-19 criteria provided, single submitter clinical testing Variant summary: GALT c.821-7A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, at least one publication reports experimental evidence that this variant affects mRNA splicing, showing the variant results in a shorted mRNA product reported as skipping of exon 9, although not verified by sequencing (e.g. Ko_2010). The variant allele was found at a frequency of 4.2e-05 in 282870 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GALT causing Galactosemia (4.2e-05 vs 0.0029), allowing no conclusion about variant significance. c.821-7A>G has been reported in the literature in multiple compound heterozygous individuals affected with Galactosemia (e.g. Ko_2010, Choi_2014). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal enzyme activity (e.g. Ko_2010). The following publications have been ascertained in the context of this evaluation (PMID: 25124065, 20547145, 34233069). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV000804257 SCV001163246 likely pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase no assertion criteria provided clinical testing

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